This proposal designates a five-year program of research aimed to provide the Principal Investigator, Dr. Michael Broman, with the mentored training necessary to become an independent physician-scientist studying the roles of changes in cardiac transcription factor signaling in atrial arrhythmogenesis. Dr. Broman is a Clinical Instructor of Medicine and Clinical Cardiac Electrophysiologist being mentored by Dr. Ivan Moskowitz, Associate Professor of Pathology, Pediatrics and Human Genetics, as well as Dr. James Liao, Professor and Section Chief of Cardiology at the University of Chicago. Atrial fibrillation (AF) is a common cardiac arrhythmia that affects more than five million Americans while carrying a substantial associated morbidity and mortality. While significant progress has been made in the understanding and treatment of this disease, the molecular basis of AF remains elusive, and likely involves multiple contributing pathways. Previous work has demonstrated that FOG-2, a transcriptional co-repressor of GATA4 signaling important in early heart development, is over-expressed in the hearts of patients with heart failure, a population prone to developing AF. A novel genetic model of inducible, cardiac specific FOG-2 expression was described by Dr. Broman that yields mice with spontaneous and persistent AF, confirmed by intracardiac recordings. Preliminary studies show that these mice develop AF before the onset of left ventricular dysfunction, while demonstrating increased late atrial fibrosis and atria thrombus formation. Further analysis in these mice has shown specific down regulation of particular potassium channel subunits in atrial myocardium prior to arrhythmia or heart failure. Dr. Broman hypothesizes that the electrical remodeling resulting from potassium channel subunit down regulation in these mice secondary to FOG-2 overexpression leads to a propensity for AF. Therefore, FOG-2 overexpression is positioned to contribute to AF in the setting of heart failure. The candidate proposes to test the role of FOG-2 overexpression in AF using the following aims: Aim 1 will investigate the direct electrophysiological consequences of FOG-2 as an inducer of electrical remodeling. Aim 2 will demonstrate links between FOG-2 and downstream target genes as mediators of AF by confirming misregulation of target gene products in a FOG-2/GATA4 dependent manner through focused promoter-reporter analysis and through high-throughput screening. Aim 3 will investigate whether pathways identified in this murine model of AF are relevant to human AF and heart failure through analysis of human atrial and ventricular tissue isolated during cardiac surgery. By establishing FOG-2 or its downstream targets as predictive markers for AF, novel preventative or therapeutic strategies can be proposed that may improve quality of life significantly for these patients.